Search

Honggang Cheng,1 Aixia Sun,2 Qingbo Guo,3 Yucai Zhang4 1Department of Gastroenterological Surgery, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng 252000, Shandong Province, People’s Republic of China; 2Department of Clinical Laboratory, Liaocheng People’s Hospital, Liaocheng Clinical School of Taishan Medical University, Liaocheng 252000, Shandong Province, People’s Republic of China; 3Department of Clinical Laboratory, Yidu Central Hospital of Weifang, Qingzhou 262500, Shandong Province, People’s Republic of China; 4Department of Health, Liaocheng People’s Hospital of Taishan Medical University, Liaocheng 252000, Shandong Province, People’s Republic of China Objective: To systematically evaluate the efficacy and safety of the combination of apatinib targeted therapy and chemotherapy (CT) in the treatment of patients with advanced gastric cancer (GC). Materials and methods: Clinical trials were extracted from PubMed, the Cochrane Library, Web of Science, EMBASE, CNKI, and the Wanfang database. Outcome measures, including therapeutic efficacy, quality of life (QOL), and adverse events, were extracted and evaluated. Results: Nineteen trials, including 1,256 advanced GC patients, were included. The results indicated that, compared with CT alone, the combination of apatinib targeted therapy with CT significantly improved the patients’ complete response rate (OR=1.85, 95% CI=1.04–3.28, P=0.04), partial response rate (OR=2.19, 95% CI=1.71–2.80, P0.05). Conclusion: The combination of apatinib targeted therapy and CT is more effective for GC treatment than CT alone. However, this combined treatment could lead to greater rates of hypertension, albuminuria, and hand–foot syndrome. Therefore, the benefits and risks should be considered before treatment. Keywords: apatinib, target therapy, chemotherapy, gastric cancer, meta-analysis

The channel sand bodies in the lower section of the Sifangtai Formation in the Songliao Basin are rich in uranium resources. The development of channel sand body distribution prediction is of great significance for guiding the exploration of sandstone-type uranium deposits. In this study, the wave-indicated inversion technology was used to predict the thickness of the sand body, the root mean square amplitude attribute was used to identify the plane shape of the river channel, and the seismic facies analysis and tracking technology of the section was used to identify the channel period and finely describe the channel distribution. The results show that there are two stages of channel sand bodies in the lower part of Sifangtai Formation, and the sand bodies are distributed in a wide range. The maximum thickness of single stage sand bodies is about 15m, with an average of 8 meters. The thickness of the sand body where the two phases of the river are superimposed is the largest, up to 28m, which is a favorable ore-bearing location revealed by current exploration.

Understanding the shared and divergent mechanisms across antidepressant (AD) classes and probiotics is critical for improving treatment for mood disorders. Here we examine the transcriptomic effects of bupropion (NDRI), desipramine (SNRI), fluoxetine (SSRI) and a probiotic formulation (Lacidofil®) on 10 regions across the mammalian brain. These treatments massively alter gene expression (on average, 2211 differentially expressed genes (DEGs) per region-treatment combination), highlighting the biological complexity of AD and probiotic action. Intersection of DEG sets against neuropsychiatric GWAS loci, sex-specific transcriptomic portraits of major depressive disorder (MDD), and mouse models of stress and depression reveals significant similarities and differences across treatments. Interestingly, molecular responses in the infralimbic cortex, basolateral amygdala and locus coeruleus are region-specific and highly similar across treatments, whilst responses in the Raphe, medial preoptic area, cingulate cortex, prelimbic cortex and ventral dentate gyrus are predominantly treatment-specific. Mechanistically, ADs concordantly downregulate immune pathways in the amygdala and ventral dentate gyrus. In contrast, protein synthesis, metabolism and synaptic signaling pathways are axes of variability among treatments. We use spatial transcriptomics to further delineate layer-specific molecular pathways and DEGs within the prefrontal cortex. Our study reveals complex AD and probiotics action on the mammalian brain and identifies treatment-specific cellular processes and gene targets associated with mood disorders., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer affecting the adult population. Median overall survival for GBM patients is poor (15 months), primarily due to high rates of tumour recurrence and the paucity of treatment options. Oncolytic virotherapy is a promising treatment alternative for GBM patients, where engineered viruses selectively infect and eradicate cancer cells by inducing cell lysis and eliciting robust anti-tumour immune response. In this study, we evaluated the oncolytic potency of live-attenuated vaccine strains of Zika virus (ZIKV-LAV) against human GBM cells in vitro. Our findings revealed that Axl and integrin α v β 5 function as cellular receptors mediating ZIKV-LAV infection in GBM cells. ZIKV-LAV strains productively infected and lysed human GBM cells but not primary endothelia and terminally differentiated neurons. Upon infection, ZIKV-LAV mediated GBM cell death via apoptosis and pyroptosis. This is the first in-depth molecular dissection of how oncolytic ZIKV infects and induces death in tumour cells., (© 2024. The Author(s).)

MicroRNAs (miRNAs) modulate mRNA expression, and their deregulation contributes to various diseases including amyotrophic lateral sclerosis (ALS). As fused in sarcoma (FUS) is a causal gene for ALS and regulates biogenesis of miRNAs, we systematically analyzed the miRNA repertoires in spinal cords and hippocampi from ALS-FUS mice to understand how FUS-dependent miRNA deregulation contributes to ALS. miRNA profiling identified differentially expressed miRNAs between different central nervous system (CNS) regions as well as disease states. Among the up-regulated miRNAs, miR-1197 targets the pro-survival pseudokinase Trib2 . A reduced TRIB2 expression was observed in iPSC-derived motor neurons from ALS patients. Pharmacological stabilization of TRIB2 protein with a clinically approved cancer drug rescues the survival of iPSC-derived human motor neurons, including those from a sporadic ALS patient. Collectively, our data indicate that miRNA profiling can be used to probe the molecular mechanisms underlying selective vulnerability, and TRIB2 is a potential therapeutic target for ALS., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Human brain development is spatially and temporally complex. Insufficient access to human brain tissue and inadequacy of animal models has limited the study of brain development and neurodegenerative diseases. Recent advancements of brain organoid technology have created novel opportunities to model human-specific neurodevelopment and brain diseases. In this review, we discuss the use of brain organoids to model the midbrain and Parkinson's disease. We critically evaluate the extent of recapitulation of PD pathology by organoids and discuss areas of future development that may lead to the model to become a next-generation, personalized therapeutic strategy for PD and beyond., (© The Author(s) 2023. Published by Oxford University Press.)

Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Aβ production and secretion., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

We examined the influence of age in beach chair position shoulder surgery and postoperative quality of recovery by conducting a single-site, observational, cohort study comparing younger aged (18-40 years) versus older aged (at least 60 years) patients admitted for elective shoulder surgery in the beach chair position. Endpoints were dichotomous return of function to each patient's individual preoperative baseline as assessed using the postoperative quality of recovery scale; measuring cognition, nociception, physiological, emotional, functional activities and overall perspective. We recruited 112 (41 younger and 71 older aged) patients. There was no statistical difference in cognitive recovery at day three postoperatively (primary outcome): 26/32 younger patients (81%) versus 43/60 (72%) older patients, P =0.45. Rates of recovery were age-dependent on domain and time frame (secondary outcomes), with older patients recovering faster in the nociceptive domain ( P =0.02), slower in the emotional domain ( P =0.02) and not different in the physiological, functional activities and overall perspective domains (all P >0.35). In conclusion, we did not show any statistically significant difference in cognitive outcomes between younger and older patients using our perioperative anaesthesia and analgesia management protocol. Irrespective of age, 70% of patients recovered by three months in all domains.

Lizards regenerate amputated tails but fail to recapitulate the dorsoventral patterning achieved during embryonic development. Regenerated lizard tails form ependymal tubes (ETs) that, like embryonic tail neural tubes (NTs), induce cartilage differentiation in surrounding cells via sonic hedgehog (Shh) signaling. However, adult ETs lack characteristically roof plate-associated structures and express Shh throughout their circumferences, resulting in the formation of unpatterned cartilage tubes. Both NTs and ETs contain neural stem cells (NSCs), but only embryonic NSC populations differentiate into roof plate identities when protected from endogenous Hedgehog signaling. NSCs were isolated from parthenogenetic lizard embryos, rendered unresponsive to Hedgehog signaling via CRISPR/Cas9 gene knockout of smoothened (Smo), and implanted back into clonally-identical adults to regulate tail regeneration. Here we report that Smo knockout embryonic NSCs oppose cartilage formation when engrafted to adult ETs, representing an important milestone in the creation of regenerated lizard tails with dorsoventrally patterned skeletal tissues., (© 2021. The Author(s).)

Objective: We utilized human midbrain-like organoids (hMLOs) generated from human pluripotent stem cells carrying glucocerebrosidase gene (GBA1) and α-synuclein (α-syn; SNCA) perturbations to investigate genotype-to-phenotype relationships in Parkinson disease, with the particular aim of recapitulating α-syn- and Lewy body-related pathologies and the process of neurodegeneration in the hMLO model., Methods: We generated and characterized hMLOs from GBA1 -/- and SNCA overexpressing isogenic embryonic stem cells and also generated Lewy body-like inclusions in GBA1/SNCA dual perturbation hMLOs and conduritol-b-epoxide-treated SNCA triplication hMLOs., Results: We identified for the first time that the loss of glucocerebrosidase, coupled with wild-type α-syn overexpression, results in a substantial accumulation of detergent-resistant, β-sheet-rich α-syn aggregates and Lewy body-like inclusions in hMLOs. These Lewy body-like inclusions exhibit a spherically symmetric morphology with an eosinophilic core, containing α-syn with ubiquitin, and can also be formed in Parkinson disease patient-derived hMLOs. We also demonstrate that impaired glucocerebrosidase function promotes the formation of Lewy body-like inclusions in hMLOs derived from patients carrying the SNCA triplication., Interpretation: Taken together, the data indicate that our hMLOs harboring 2 major risk factors (glucocerebrosidase deficiency and wild-type α-syn overproduction) of Parkinson disease provide a tractable model to further elucidate the underlying mechanisms for progressive Lewy body formation. ANN NEUROL 2021;90:490-505., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The combination of single-cell RNA sequencing with CRISPR inhibition/activation provides a high-throughput approach to simultaneously study the effects of hundreds if not thousands of gene perturbations in a single experiment. One recent development in CRISPR-based single-cell techniques introduces a feature barcoding technology that allows for the simultaneous capture of mRNA and guide RNA (gRNA) from the same cell. This is achieved by introducing a capture sequence, whose complement can be incorporated into each gRNA and that can be used to amplify these features prior to sequencing. However, because the technology is in its infancy, there is little information available on how such experimental parameters can be optimized. To overcome this, we varied the capture sequence, capture sequence position, and gRNA backbone to identify an optimal gRNA scaffold for CRISPR activation gene perturbation studies. We provide a report on our screening approach along with our observations and recommendations for future use.

Damaged articular cartilage has limited self-healing capabilities, leading to degeneration that affects millions of people. Although cartilage tissue engineering is considered a promising approach for treatment, robust and long-term chondrogenesis within a 3-dimensional (3D) scaffold remains a major challenge for complete regeneration. Most current approaches involve incorporation of transforming growth factor-β (TGF-β) into the scaffold, but have limited utility owing to the short functional half-life and/or rapid clearance of TGF-β. In this study, we have tested the incorporation of graphene oxide nanosheets (GO) within a photopolymerizable poly-D, l-lactic acid/polyethylene glycol (PDLLA) hydrogel, for its applicability in sustained release of the chondroinductive growth factor TGF-β3. We found that with GO incorporation, the hydrogel scaffold (GO/PDLLA) exhibited enhanced initial mechanical strength, i.e., increased compressive modulus, and supported long-term, sustained release of TGF-β3 for up to 4 weeks. In addition, human bone marrow-derived mesenchymal stem cells (hBMSCs) seeded within TGF-β3 loaded GO/PDLLA hydrogels displayed high cell viability and improved chondrogenesis in a TGF-β3 concentration-dependent manner. hBMSCs cultured in GO/PDLLA also demonstrated significantly higher chondrogenic gene expression, including aggrecan, collagen type II and SOX9, and cartilage matrix production when compared to cultures maintained in GO-free scaffolds containing equivalent amounts of TGF-β3. Upon subcutaneous implantation in vivo, hBMSC-seeded TGF-β3-GO/PDLLA hydrogel constructs displayed considerably greater cartilage matrix than their TGF-β3/PDLLA counterparts without GO. Taken together, these findings support the potential application of GO in optimizing TGF-β3 induced hBMSC chondrogenesis for cartilage tissue engineering. STATEMENT OF SIGNIFICANCE: In this work, we have developed a graphene oxide (GO) incorporated, photocrosslinked PDLLA hybrid hydrogel for localized delivery and sustained release of loaded TGF-β3 to seeded cells. The incorporation of GO in PDLLA hydrogel suppressed the burst release of TGF-β3, and significantly prolonged the retention time of the TGF-β3 initially loaded in the hydrogel. Additionally, the GO improved the initial compressive strength of the hydrogel. Both in vitro analyses and in vivo implantation results showed that the GO/PDLLA constructs seeded with human mesenchymal stem cells (hMSCs) showed significantly higher cartilage formation, compared to GO-free scaffolds containing equivalent amount of TGF-β3. Findings from this work suggest the potential application of the GO-TGF/PDLLA hydrogel as a functional scaffold for hMSC-based cartilage tissue engineering., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier Ltd.)

Disruptions in the ubiquitin protein ligase E3A ( UBE3A ) gene cause Angelman syndrome (AS). Whereas AS model mice have associated synaptic dysfunction and altered plasticity with abnormal behavior, whether similar or other mechanisms contribute to network hyperactivity and epilepsy susceptibility in AS patients remains unclear. Using human neurons and brain organoids, we demonstrate that UBE3A suppresses neuronal hyperexcitability via ubiquitin-mediated degradation of calcium- and voltage-dependent big potassium (BK) channels. We provide evidence that augmented BK channel activity manifests as increased intrinsic excitability in individual neurons and subsequent network synchronization. BK antagonists normalized neuronal excitability in both human and mouse neurons and ameliorated seizure susceptibility in an AS mouse model. Our findings suggest that BK channelopathy underlies epilepsy in AS and support the use of human cells to model human developmental diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Reservoir sediments act as important receivers and sources for nutrients in the overlaying water. To determine the sediments adsorption and release characteristics and their impacts on water quality, surface sediments samples collected from Biliuhe reservoir in August 2015 were studied through simulation experiments in a laboratory. The results demonstrated that the equilibrium concentrations (EC 0 ) of ammonia nitrogen (NH 4 + -N) and total phosphorus (TP) were 8.29 mg/L and 0.025 mg/L, respectively, which were both higher than the average concentrations in the overlying water. Therefore, the sediments of Biliuhe reservoir mainly acted as the pollution sources for NH 4 + -N and TP, and the release to water showed a seasonal variation. When potential release amounts were considered, the average concentrations of NH 4 + -N and TP in the overlaying water could reach 6.4 mg/L and 0.21 mg/L, respectively, which significantly exceeded the current contents. Further, water quality exhibited a decreased tendency after taking the release potential of nutrients into account of water quality assessment. Among the samples, 42% and 33% of them in summer and autumn exceeded the third level of the National Surface Water Quality Standards of China (GB3838-2002). The results indicated that sediments release potential had an unignored influence on water quality during various seasons., Competing Interests: The authors declare no conflicts of interest.

An essential structure in nerve regeneration within engineered conduits is the "nerve bridge" initiated by centrally migrating Schwann cells in response to chemokine gradients. Introducing exogenous cells secreting neurotrophic factors aims to augment this repair process, but conventional cell-seeding methods fail to produce a directional chemokine gradient. We report a versatile method to encapsulate cells within conduit walls, allowing for reproducible control of spatial distribution along the conduit. Conduits with stem cells encapsulated within the central third possessed markedly different cell distribution and retention over 6 weeks in vivo, compared to standard cell lumen injection. Such a construct promoted Schwann cell migration centrally, and at 16 weeks rats presented with significantly enhanced function and axonal myelination. The method of utilizing a spatially restricted cell secretome departs from traditional homogeneous cell loading, and presents new approaches for studying and maximizing the potential of cell application in peripheral nerve repair., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Coiled-coil-helix-coiled-coil-helix domain containing protein 2 (CHCHD2) mutations were linked with autosomal dominant Parkinson's disease (PD) and recently, Alzheimer's disease/frontotemporal dementia. In the current study, we generated isogenic human embryonic stem cell (hESC) lines harboring PD-associated CHCHD2 mutation R145Q or Q126X via clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) method, aiming to unravel pathophysiologic mechanism and seek potential intervention strategy against CHCHD2 mutant-caused defects. By engaging super-resolution microscopy, we identified a physical proximity and similar distribution pattern of CHCHD2 along mitochondria with mitochondrial contact site and cristae organizing system (MICOS), a large protein complex maintaining mitochondria cristae. Isogenic hESCs and differentiated neural progenitor cells (NPCs) harboring CHCHD2 R145Q or Q126X mutation showed impaired mitochondria function, reduced CHCHD2 and MICOS components and exhibited nearly hollow mitochondria with reduced cristae. Furthermore, PD-linked CHCHD2 mutations lost their interaction with coiled-coil-helix-coiled-coil-helix domain containing protein 10 (CHCHD10), while transient knockdown of either CHCHD2 or CHCHD10 reduced MICOS and mitochondria cristae. Importantly, a specific mitochondria-targeted peptide, Elamipretide/MTP-131, now tested in phase 3 clinical trials for mitochondrial diseases, was found to enhance CHCHD2 with MICOS and mitochondria oxidative phosphorylation enzymes in isogenic NPCs harboring heterozygous R145Q, suggesting that Elamipretide is able to attenuate CHCHD2 R145Q-induced mitochondria dysfunction. Taken together, our results suggested CHCHD2-CHCHD10 complex may be a novel therapeutic target for PD and related neurodegenerative disorders, and Elamipretide may benefit CHCHD2 mutation-linked PD., (© The Author(s) 2018. Published by Oxford University Press.)

Cell-loaded hydrogels are frequently applied in cartilage tissue engineering for their biocompatibility, ease of application, and ability to conform to various defect sites. As a bioactive adjunct to the biomaterial, transforming growth factor beta (TGF-β) has been shown to be essential for cell differentiation into a chondrocyte phenotype and maintenance thereof, but the low amounts of endogenous TGF-β in the in vivo joint microenvironment necessitate a mechanism for controlled delivery and release of this growth factor. In this study, TGF-β3 was directly loaded with human bone marrow-derived mesenchymal stem cells (MSCs) into poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA-PEG) hydrogel, or PDLLA-PEG with the addition of hyaluronic acid (PDLLA/HA), and cultured in vitro. We hypothesize that the inclusion of HA within PDLLA-PEG would result in a controlled release of the loaded TGF-β3 and lead to a robust cartilage formation without the use of TGF-β3 in the culture medium. ELISA analysis showed that TGF-β3 release was effectively slowed by HA incorporation, and retention of TGF-β3 in the PDLLA/HA scaffold was detected by immunohistochemistry for up to 3 weeks. By means of both in vitro culture and in vivo implantation, we found that sulfated glycosaminoglycan production was higher in PDLLA/HA groups with homogenous distribution throughout the scaffold than PDLLA groups. Finally, with an optimal loading of TGF-β3 at 10 μg/mL, as determined by RT-PCR and glycosaminoglycan production, an almost twofold increase in Young's modulus of the construct was seen over a 4-week period compared to TGF-β3 delivery in the culture medium. Taken together, our results indicate that the direct loading of TGF-β3 and stem cells in PDLLA/HA has the potential to be a one-step point-of-care treatment for cartilage injury. STATEMENT OF SIGNIFICANCE: Stem cell-seeded hydrogels are commonly used in cell-based cartilage tissue engineering, but they generally fail to possess physiologically relevant mechanical properties suitable for loading. Moreover, degradation of the hydrogel in vivo with time further decreases mechanical suitability of the hydrogel due in part to the lack of TGF-β3 signaling. In this study, we demonstrated that incorporation of hyaluronic acid (HA) into a physiologically stiff PDLLA-PEG hydrogel allowed for slow release of one-time preloaded TGF-β3, and when loaded with adult mesenchymal stem cells and cultured in vitro, it resulted in higher chondrogenic gene expression and constructs of significantly higher mechanical strength than constructs cultured in conventional TGF-β3-supplemented medium. Similar effects were also observed in constructs implanted in vivo. Our results indicate that direct loading of TGF-β3 combined with HA in the physiologically stiff PDLLA-PEG hydrogel has the potential to be used for one-step point-of-care treatment of cartilage injury., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Studies have identified multiple risk factors for development of cognitive decline after surgery. Impaired cerebrovascular autoregulation may be a contributor to postoperative cognitive decline., Methods: One hundred and forty patients admitted for major elective noncardiac surgery were recruited. Near-infrared spectroscopy was used to calculate the tissue oxygenation index of dynamic autoregulation (TOx). The primary endpoint was Day 3 cognitive recovery as assessed using the Postoperative Quality of Recovery Scale. The secondary endpoint was a combined major adverse event of death, acute myocardial infarction, cardiac arrest, stroke, pulmonary embolism, sepsis, and acute kidney injury at Day 30., Results: Higher optimal TOx values, signifying impaired autoregulation, were associated with worse outcomes. Patients who cognitively recovered at Day 3 (n = 47) had lower optimal TOx values (TOx opt ) than patients who did not recover (n = 22): 0.06 (0.24) vs 0.18 (0.16) (mean [SD]), P = 0.02. Patients who did not suffer a major adverse event (n = 102) had lower TOx opt than patients who did (n = 17): 0.09 (0.21) vs 0.20 (0.27), P = 0.04. When dichotomized as having impaired or intact autoregulation based on TOx opt levels, a value of TOx opt ≥0.1 correctly identified 72.7% of patients who did not cognitively recover, OR 3.3 (1.1-9.9) (Odds ratio, [95% CI]), P = 0.03. TOx opt ≥0.1 correctly identified 82.4% of patients who suffered a major adverse event, OR 4.7 (1.3-17.2), P = 0.02., Conclusions: In older and higher risk patients having major noncardiac surgery, impaired cerebrovascular autoregulation was associated with failure of cognitive recovery in the early postoperative period and with 1-month mortality and morbidity., (© 2018 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

While lizards and salamanders both exhibit the ability to regenerate amputated tails, the outcomes achieved by each are markedly different. Salamanders, such as Ambystoma mexicanum , regenerate nearly identical copies of original tails. Regenerated lizard tails, however, exhibit important morphological differences compared with originals. Some of these differences concern dorsoventral patterning of regenerated skeletal and spinal cord tissues; regenerated salamander tail tissues exhibit dorsoventral patterning, while regrown lizard tissues do not. Additionally, regenerated lizard tails lack characteristically roof plate-associated structures, such as dorsal root ganglia. We hypothesized that differences in neural stem cells (NSCs) found in the ependyma of regenerated spinal cords account for these divergent regenerative outcomes. Through a combination of immunofluorescent staining, RT-PCR, hedgehog regulation, and transcriptome analysis, we analyzed NSC-dependent tail regeneration. Both salamander and lizard Sox2 + NSCs form neurospheres in culture. While salamander neurospheres exhibit default roof plate identity, lizard neurospheres exhibit default floor plate. Hedgehog signaling regulates dorsalization/ventralization of salamander, but not lizard, NSCs. Examination of NSC differentiation potential in vitro showed that salamander NSCs are capable of neural differentiation into multiple lineages, whereas lizard NSCs are not, which was confirmed by in vivo spinal cord transplantations. Finally, salamander NSCs xenogeneically transplanted into regenerating lizard tail spinal cords were influenced by native lizard NSC hedgehog signals, which favored salamander NSC floor plate differentiation. These findings suggest that NSCs in regenerated lizard and salamander spinal cords are distinct cell populations, and these differences contribute to the vastly different outcomes observed in tail regeneration., Competing Interests: The authors declare no conflict of interest.

Purpose of the Review: This manuscript discusses wound healing as a component of epimorphic regeneration and the role of the immune system in this process., Recent Findings: Epimorphic regeneration involves formation of a blastema, a mass of undifferentiated cells capable of giving rise to the regenerated tissues. The apical epithelial cap plays an important role in blastemal formation., Summary: True regeneration is rarely observed in mammals. With the exception of transgenic strains, tissue repair in mammals usually leads to non-functional fibrotic tissue formation. In contrast, a number of lower order species including planarians, salamanders, and reptiles, have the ability to overcome the burden of scarring and tissue loss through complex adaptations that allow them to regenerate various anatomic structures through epimorphic regeneration. Blastemal cells have been suggested to originate via various mechanisms including de-differentiation, transdifferentiation, migration of pre-existing adult stem cell niches, and combinations of these.

Graphene-based nanomaterials have been applied as biomaterials to enhance stem cell adhesion, growth and differentiation by serving as nanocarriers for growth factors or other small molecules. However, the direct effect of graphene oxide (GO) itself on stem cells, in the absence of exogenous differentiation inductive factors, has not been tested. In this study, we loaded GO nanosheets and human bone marrow-derived mesenchymal stem cells (hBMSC) into a photopolymerizable poly-d,l-lactic acid/polyethylene glycol (PDLLA) hydrogel, a robust chondrosupportive scaffold recently developed in our laboratory, and assessed hBMSC differentiation along the chondrogenic lineage without supplemental chondroinductive factors. We first examined the effect of GO incorporation on the mechanical properties of constructs, and observed that the GO-containing constructs (GO/PDLLA) exhibited enhanced compressive modulus in a GO concentration dependent manner. hBMSCs cultured in GO/PDLLA maintained high cell viability (>95%), indicating minimal cytotoxicity of GO. Importantly, compared to those encapsulated in PDLLA hydrogel, hBMSCs within GO/PDLLA showed significantly higher level of gene expression of the cartilage matrix genes, aggrecan and collagen type II, and produced more cartilage matrix. In addition, the pro-chondrogenesis effect of GO increased with increasing GO concentration. Immunohistochemical results suggested that GO-enhanced hBMSC chondrogenesis was correlated with enriched sequestration of insulin, a necessary supplement known to have pro-chondrogenesis effects on hBMSC. Taken together, these findings demonstrate the utility of using GO to improve the mechanical properties and chondrogenic differentiation state of MSC-laden, engineered hydrogel constructs, without the use of exogenous growth factors, thus representing a potentially promising, biologics-free approach for cartilage tissue engineering.

Three-dimensional (3D) in vitro neural tissue models provide a better recapitulation of in vivo cell-cell and cell-extracellular matrix interactions than conventional two-dimensional (2D) cultures. Therefore, the former is believed to have great potential for both mechanistic and translational studies. In this paper, we review the recent developments in 3D in vitro neural tissue models, with a particular focus on the emerging bioprinted tissue structures. We draw on specific examples to describe the merits and limitations of each model, in terms of different applications. Bioprinting offers a revolutionary approach for constructing repeatable and controllable 3D in vitro neural tissues with diverse cell types, complex microscale features and tissue level responses. Further advances in bioprinting research would likely consolidate existing models and generate complex neural tissue structures bearing higher fidelity, which is ultimately useful for probing disease-specific mechanisms, facilitating development of novel therapeutics and promoting neural regeneration., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The recent technology of 3D cultures of cellular aggregates derived from human stem cells have led to the emergence of tissue-like structures of various organs including the brain. Brain organoids bear molecular and structural resemblance with developing human brains, and have been demonstrated to recapitulate several physiological and pathological functions of the brain. Here we provide an overview of the development of brain organoids for the clinical community, focusing on the current status of the field with an critical evaluation of its translational value.

Adult tissue-derived mesenchymal stem cells (MSCs) are known to produce a number of bioactive factors, including neurotrophic growth factors, capable of supporting and improving nerve regeneration. However, with a finite culture expansion capacity, MSCs are inherently limited in their lifespan and use. We examined here the potential utility of an alternative, mesenchymal-like cell source, derived from induced pluripotent stem cells, termed induced mesenchymal progenitor cells (MiMPCs). We found that several genes were upregulated and proteins were produced in MiMPCs that matched those previously reported for MSCs. Like MSCs, the MiMPCs secreted various neurotrophic and neuroprotective factors, including brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), osteopontin, and osteonectin, and promoted neurite outgrowth in chick embryonic dorsal root ganglia (DRG) cultures compared with control cultures. Cotreatment with a pharmacological Trk-receptor inhibitor did not result in significant decrease in MiMPC-induced neurite outgrowth, which was however inhibited upon Jak/STAT3 blockade. These findings suggest that the MiMPC induction of DRG neurite outgrowth is unlikely to be solely dependent on BDNF, but instead Jak/STAT3 activation by IL-6 and/or LIF is likely to be critical neurotrophic signaling pathways of the MiMPC secretome. Taken together, these findings suggest MiMPCs as a renewable, candidate source of therapeutic cells and a potential alternative to MSCs for peripheral nerve repair, in view of their ability to promote nerve growth by producing many of the same growth factors and cytokines as Schwann cells and signaling through critical neurotrophic pathways. Stem Cells Translational Medicine 2018;7:45-58., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

Three-dimensional hydrogel constructs incorporated with live stem cells that support chondrogenic differentiation and maintenance offer a promising regenerative route towards addressing the limited self-repair capabilities of articular cartilage. In particular, hydrogel scaffolds that augment chondrogenesis and recapitulate the native physical properties of cartilage, such as compressive strength, can potentially be applied in point-of-care procedures. We report here the synthesis of two new materials, [poly-l-lactic acid/polyethylene glycol/poly-l-lactic acid] (PLLA-PEG 1000) and [poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid] (PDLLA-PEG 1000), that are biodegradable, biocompatible (>80% viability post fabrication), and possess high, physiologically relevant mechanical strength (∼1500 to 1800kPa). This study examined the effects of physiologically relevant cell densities (4, 8, 20, and 50×10 6 /mL) and hydrogel stiffnesses (∼150kPa to∼1500kPa Young's moduli) on chondrogenesis of human bone marrow stem cells incorporated in hydrogel constructs fabricated with these materials and a previously characterized PDLLA-PEG 4000. Results showed that 20×10 6 cells/mL, under a static culture condition, was the most efficient cell seeding density for extracellular matrix (ECM) production on the basis of hydroxyproline and glycosaminoglycan content. Interestingly, material stiffness did not significantly affect chondrogenesis, but rather material concentration was correlated to chondrogenesis with increasing levels at lower concentrations based on ECM production, chondrogenic gene expression, and histological analysis. These findings establish optimal cell densities for chondrogenesis within three-dimensional cell-incorporated hydrogels, inform hydrogel material development for cartilage tissue engineering, and demonstrate the efficacy and potential utility of PDLLA-PEG 1000 for point-of-care treatment of cartilage defects., Statement of Significance: Engineering cartilage with physiologically relevant mechanical properties for point-of-care applications represents a major challenge in orthopedics, given the generally low mechanical strengths of traditional hydrogels used in cartilage tissue engineering. In this study, we characterized a new material that possesses high mechanical strength similar to native cartilage, and determined the optimal cell density and scaffold stiffness to achieve the most efficient chondrogenic response from seeded human bone marrow stem cells. Results show robust chondrogenesis and strongly suggest the potential of this material to be applied clinically for point-of-care repair of cartilage defects., (Copyright © 2017. Published by Elsevier Ltd.)

Gamma-aminobutyric acid (GABA)-releasing interneurons play an important modulatory role in the cortex and have been implicated in multiple neurological disorders. Patient-derived interneurons could provide a foundation for studying the pathogenesis of these diseases as well as for identifying potential therapeutic targets. Here, we identified a set of genetic factors that could robustly induce human pluripotent stem cells (hPSCs) into GABAergic neurons (iGNs) with high efficiency. We demonstrated that the human iGNs express neurochemical markers and exhibit mature electrophysiological properties within 6-8 weeks. Furthermore, in vitro, iGNs could form functional synapses with other iGNs or with human-induced glutamatergic neurons (iENs). Upon transplantation into immunodeficient mice, human iGNs underwent synaptic maturation and integration into host neural circuits. Taken together, our rapid and highly efficient single-step protocol to generate iGNs may be useful to both mechanistic and translational studies of human interneurons., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The poor self-healing ability of cartilage necessitates the development of methods for cartilage regeneration. Scaffold construction with live stem cell incorporation and subsequent differentiation presents a promising route. Projection stereolithography (PSL) offers high resolution and processing speed as well as the ability to fabricate scaffolds that precisely fit the anatomy of cartilage defects using medical imaging as the design template. We report here the use of a visible-light-based PSL (VL-PSL) system to encapsulate human adipose-derived stem cells (hASCs) into a biodegradable polymer [poly-d,l-lactic acid/polyethylene glycol/poly-d,l-lactic acid (PDLLA-PEG)]/hyaluronic acid (HA) matrix to produce live cell constructs with customized architectures. After fabrication, hASCs showed high viability (84%) and were uniformly distributed throughout the constructs, which possessed high mechanical properties with a compressive modulus of 780 kPa. The hASC-seeded constructs were then cultured in control or TGF-β3-containing chondrogenic medium for up to 28 days. In chondrogenic medium-treated group (TGF-β3 group), hASCs maintained 77% viability and expressed chondrogenic genes Sox9, collagen type II, and aggrecan at 11, 232, and 2.29 × 10(5) fold increases, respectively compared to levels at day 0 in non-chondrogenic medium. The TGF-β3 group also produced a collagen type II and glycosaminoglycan-rich extracellular matrix, detected by immunohistochemistry, Alcian blue staining, and Safranin O staining suggesting robust chondrogenesis within the scaffold. Without chondroinductive addition (Control group), cell viability decreased with time (65% at 28 days) and showed poor cartilage matrix deposition. After 28 days, mechanical strength of the TGF-β3 group remained high at 240 kPa. Thus, the PSL and PDLLA-PEG/HA-based fabrication method using adult stem cells is a promising approach in producing mechanically competent engineered cartilage for joint cartilage resurfacing.

Aim: To evaluate the outcomes of patients with medium-sized hepatocellular carcinoma (HCC) who underwent percutaneous microwave ablation (MWA)., Methods: We retrospectively reviewed all patients with a single medium-sized HCC who underwent percutaneous MWA from January 2010 to January 2013. Technical success, technical effectiveness and complications were subsequently observed. Survival curves were constructed using the Kaplan-Meier method. The Cox proportional hazards model was fitted to each variable. The relative prognostic significance of the variables for predicting overall survival rate, recurrence-free survival rate and local tumor recurrence(s) was assessed using univariate analysis. All variables with a P value < 0.20 were subjected to multivariate analysis., Results: The study included 182 patients (mean age, 58 years; age range: 22-86 years) with a single HCC (mean size, 3.72 ± 0.54 cm; range: 3.02-5.00 cm). The estimated technical effectiveness rate was 93% in 182 patients. The major complication rate was 2.7% (5/182), including liver abscess in 4 cases, and abdominal bleeding at the puncture site in 1 case. Thirty-day mortality rate was 0.5% (1/182). One patient died due to liver abscess-related septicemia. Cumulative recurrence-free survival and overall survival (OS) rates were 51%, 36%, 27% and 89%, 74%, 60% at 1, 2, and 3 years, respectively. Age (P = 0.017) and tumor diameter (P = 0.029) were independent factors associated with local tumor recurrence. None of the factors had a statistically significant impact on recurrence-free survival. Serum albumin level (P = 0.009) and new lesion(s) (P = 0.029) were independently associated with OS., Conclusion: Percutaneous MWA is a relatively safe and effective treatment for patients with medium-sized HCC.

NANOG has been extensively researched since its discovery by Chambers et al. NANOG is a homeodomain transcription factor and an essential regulator of embryonic stem cell (ESC) self-renewal, which inhibits differentiation. Cancer stem cells (CSCs) are a small subset of cells that are thought to drive uncontrolled tumor growth; CSCs retain the tumor capabilities of self-renewal and propagation. The existence of CSCs was recently shown by direct experimental evidence. NANOG is expressed in CSCs and ESCs, although it remains unclear whether ESCs and CSCs share similar mechanisms in the regulation of physical and biological processes. Several studies suggest that the expression level of NANOG is high in cancer tissues and low or absent in normal tissues. High levels of NANOG expression are associated with advanced stages of cancer and a poor prognosis, indicating that it plays a vital role in tumor transformation, tumorigenesis, and tumor metastasis. NANOG is part of a complex regulatory network that controls cell fate determination, proliferation, and apoptosis. NANOG cooperates with other regulators, such as microflora, transcription factors, and kinases, in cancer cells. NANOG might have a promising future in anti-cancer and other therapeutic treatments, which could improve human health.

Development of novel treatments and diagnostic tools for psychiatric illness has been hindered by the absence of cellular models of disease. With the advent of cellular reprogramming, it may be possible to recapitulate the disease biology of psychiatric disorders using patient skin cells transdifferentiated to neurons. However, efficiently identifying and characterizing relevant neuronal phenotypes in the absence of well-defined pathophysiology remains a challenge. In this study, we collected fibroblast samples from patients with bipolar 1 disorder, characterized by their lithium response (n=12), and healthy control subjects (n=6). We identified a cellular phenotype in reprogrammed neurons using a label-free imaging assay based on a nanostructured photonic crystal biosensor and found that an optical measure of cell adhesion was associated with clinical response to lithium treatment. This cellular phenotype may represent a useful biomarker to evaluate drug response and screen for novel therapeutics.

Background: Repeated hepatic resection (HR) and thermal ablation therapy (TAT) are increasingly being used to treat recurrent intrahepatic cholangiocarcinoma (RICC). This study compared the efficacy and safety of these procedures for RICC treatment., Methods: Patients were studied retrospectively after curative resection of RICCs by repeated HR (n = 32) or TAT (n = 77). Treatment effectiveness and prognosis were compared between the two treatment groups., Results: The repeated HR and TAT groups did not differ in their overall survival (OS; p = 0.996) or disease-free survival (DFS; p = 0.692) rates. However, among patients with recurrent tumors >3 cm in diameter, patients in the repeated HR group had a higher OS rate than patients in the TAT group (p = 0.037). The number of recurrent tumors and the recurrence interval were significant prognostic factors for OS. The major complications incidence rate was greater in the repeated HR group than in the TAT group (p < 0.001)., Conclusions: Repeated HR and TAT are both effective treatments for RICC with similar overall efficacies. TAT should be preferred in any cases when the RICC is ≤3 cm in diameter and technically feasible. However, for large tumors (>3 cm), repeated HR may be a better choice.

Objectives: Virtual Touch tissue quantification (VTQ) is a quantified ultrasound (US) acoustic radiation force impulse (ARFI) imaging method that provides numerical measurements (wave-velocity values) of tissue stiffness. The purpose of this study was to detect whether VTQ could be applied to differentiate between benign and malignant thyroid lesions., Methods: Healthy subjects' thyroid tissue and thyroid lesions were examined by VTQ to analyze their elasticity after conventional ultrasound. All the thyroid lesions were analyzed pathologically after surgery and correlated the VTQ values with the pathological results., Results: The VTQ value of healthy thyroid tissue, the benign lesions, and the malignant lesions were 1.69 ± 0.41 m/s, 2.03 ± 0.42 m/s, and 3.10 ± 1.08 m/s, respectively. The VTQ value of the malignant lesions was higher than that of the healthy thyroid tissue and the benign lesions (both p<0.001). The VTQ value of the benign lesions was higher than that of the healthy thyroid tissue (p<0.001). With a cutoff value of 2.42 m/s, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for differentiating between the benign and the malignancy lesions were 80.00%, 89.23%, 87.05%, 69.56%, and 93.54%, respectively., Conclusions: VTQ could provide quantitative elasticity measurements, which might play an important role in differentiating between benign and malignant thyroid lesions., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Mammalian neural development has been traditionally studied in the context of evolutionarily conserved signaling pathways and neurogenic transcription factors. Recent studies suggest that microRNAs, a group of highly conserved noncoding regulatory small RNAs also play essential roles in neural development and neuronal function. A part of their action in the developing nervous system is to regulate subunit compositions of BAF complexes (ATP-dependent chromatin remodeling complexes), which appear to have dedicated functions during neural development. Intriguingly, ectopic expression of a set of brain-enriched microRNAs, miR-9/9* and miR-124 that promote the assembly of neuron-specific BAF complexes, converts the nonneuronal fate of human dermal fibroblasts towards postmitotic neurons, thereby revealing a previously unappreciated instructive role of these microRNAs. In addition to these global effects, accumulating evidence indicates that many microRNAs could also function locally, such as at the growth cone or at synapses modulating synaptic activity and neuronal connectivity. Here we discuss some of the recent findings about microRNAs' activity in regulating various developmental stages of neurons., (Copyright © 2013. Published by Elsevier Ltd.)

Monolayer protected gold nanoparticles (AuNPs) modified with a 3-aryl-3-(trifluoromethyl)diazirine functionality at its terminus (Diaz-AuNPs, 3.9 nm) were prepared and irradiated in the presence of two very different substrates, reduced graphene and glass. Upon irradiation, the terminal diazirine group loses nitrogen to generate a reactive carbene at the interface of the AuNPs that can then undergo addition or insertion reactions with functional groups on the graphene or glass surfaces, leading to the formation of graphene-AuNP and glass-AuNP hybrids, respectively. The AuNP hybrids were characterized using TEM, XRD, XPS, AFM, and UV-vis spectroscopy. Control experiments done in the absence of irradiation demonstrate that carbene activation is required for incorporation of significant AuNP onto the materials. The AuNP hybrids are robust and stable to excessive washing and centrifugation supporting the covalent nature of the interaction between the AuNP and the graphene or silicate glass substrates. Because the formation of the composite is light activated, it lends itself to photopatterning; this application is demonstrated for making the glass-AuNP composites.

Neurogenic transcription factors and evolutionarily conserved signalling pathways have been found to be instrumental in the formation of neurons. However, the instructive role of microRNAs (miRNAs) in neurogenesis remains unexplored. We recently discovered that miR-9* and miR-124 instruct compositional changes of SWI/SNF-like BAF chromatin-remodelling complexes, a process important for neuronal differentiation and function. Nearing mitotic exit of neural progenitors, miR-9* and miR-124 repress the BAF53a subunit of the neural-progenitor (np)BAF chromatin-remodelling complex. After mitotic exit, BAF53a is replaced by BAF53b, and BAF45a by BAF45b and BAF45c, which are then incorporated into neuron-specific (n)BAF complexes essential for post-mitotic functions. Because miR-9/9* and miR-124 also control multiple genes regulating neuronal differentiation and function, we proposed that these miRNAs might contribute to neuronal fates. Here we show that expression of miR-9/9* and miR-124 (miR-9/9*-124) in human fibroblasts induces their conversion into neurons, a process facilitated by NEUROD2. Further addition of neurogenic transcription factors ASCL1 and MYT1L enhances the rate of conversion and the maturation of the converted neurons, whereas expression of these transcription factors alone without miR-9/9*-124 was ineffective. These studies indicate that the genetic circuitry involving miR-9/9*-124 can have an instructive role in neural fate determination.

The RUNX1/AML1 gene encodes a transcription factor essential for the generation of hematopoietic stem cells and is frequently targeted in human leukemia. In human RUNX1-related leukemias, the RAS pathway is often concurrently mutated, but the mechanism of the synergism remains elusive. Here, we found that inactivation of Runx1 in mouse bone marrow cells results in an increase in the stem/progenitor cell fraction due to suppression of apoptosis and elevated expression of the polycomb gene Bmi-1, which is important for stem cell self-renewal. Introduction of oncogenic N-RAS into wild-type cells, in contrast, reduced the stem/progenitor cell fraction because of senescence, apoptosis, and differentiation. Such detrimental events presumably occurred because of the cellular fail-safe program, although hyperproliferation was initially induced by an oncogenic stimulus. Runx1 insufficiency appears to impair such a fail-safe mechanism, particularly in the stem/progenitor cells, thereby supporting the clonal maintenance of leukemia-initiating cells expressing an activated oncogene. Disclosure of potential conflicts of interest is found at the end of this article.

Objective: To study whether the anti-apoptotic action is reversed by tetrandrine in a combination with vincristine in human breast carcinoma MCF-7 multidrug-resistant cells., Method: Chromatin condensation was observed by co-staining of fluorescent dyes Hoechst 33342 and propidium iodide; and G1 sub-peak was detected by flow cytometry. Apoptotic cells were detected with TUNEL method. Cellular free ca2+ was determined with Fluo-3 staining method., Result: Two types of chromatin condensation were observed after the sensitive and drug-resistant MCF-7 cells were treated with an antitumor drug vincristine 5 mumol.L-1 for 24 h. The number of cell with chromatin condensation was obviously reduced in the drug-resistant cells treated with the same concentration of vincristine, as compared with the sensitive MCF-7 cells. The number of the apoptotic cells was increased by a combination of non-cytotoxic tetrandrine 20 mumol.L-1 and vincristine in both the sensitive and drug-resistant cells, which was confirmed with fluorescent indication and TUNEL method. The increment of introcellular free Ca2+ level in the cells treated with tetrandrine in a combination of vincristine was detected with Fluo-3 staining method., Conclusion: The anti-apoptotic action of human breast carcinoma MCF-7 cells can be effectively reversed by tetrandrine.

Aim: To investigate the poteintation of vincristine-induecd apoptosis by tetrandrine, neferine and dauricine isolated from Chinese medicinal plants in the human mammary MCF-7 multidrug resistant cells., Methods: The apoptotic cells were detected by fluorescent staining of a combination of Hoechst 33342 and propidium iodide (PI), flow cytometry and agarose electrophoresis., Results: The apoptotic cells induced by vincristine alone accounted for about 10% of all the cancer cells, while the percentage of apoptotic cells induced by a combination of vincristine with tetrandrine, neferine, or dauricine was found to be significantly higher than that by vincristine alone, and their reversal effects were positively correlated with the drug concentration and the exposure time. In addition, tetrandrine was shown to be the most potent in the reversal efficacy among the three compounds to be tested for apoptosis in vitro., Conclusion: Tetrandrine, neferine and dauricine showed obvious potenitiation of vincristine-induced apoptosis in the human mammary MCF-7 multidrug-resistant cells.

Aim: To study the interaction between tetrandrine (Tet) and doxorubicin (Dox) or vincristine (Vin) against human breast cancer cell lines MCF-7 and MCF-7/Dox or human nasopharyngeal cancer cell lines KB and KBV200 in vitro., Methods: Anticancer activities of a drug alone and a drug combination of Tet and Dox or Vin were determined by tetrazolium (MTT) method. The interaction between Tet and Dox or Vin was evaluated by both a value of a sum of fractional inhibitory concentration (SFIC) and an isobologram method., Results: The SFIC values of the three-different-ratio combinations between Tet and Dox ranged from 0.14 to 0.38 for MCF-7, and 0.10 to 0.29 for MCF-7/Dox; those of Tet-Vin combinations ranged from 0.21 to 0.37 for KB, and 0.32 to 0.63 for KBV200. All the SFIC values of the combination between Tet and Dox or Vin were less than 1.0 when the 3 ratios of the 2 drugs in combination were used, and the shapes of isobolic curves obtained from the combination were concave., Conclusion: The interaction between Tet and Dox or Vin against the human cancer cells was markedly synergistic.

The effects of scoparone (Sco), tetramethylpyrazine (TMP), and papaverine (Pap) on hemodynamics were compared in anesthetized rabbits. Three dosage levels (1.25, 2.5, 5 mg.kg-1, iv) were used for each agent. Sco lowered the blood pressure (BP), increased the cerebral blood flow (CBF) dose-dependently, but did not show significant influence on the femoral artery blood flow (FBF), the maximal decrease of BP, and the maximal increases of CBF being 15% and 20% of the control, respectively. In contrast, TMP raised the BP as well as increased the CBF and FBF simultaneously. Pap, however, lowered the BP, slightly increased the CBF and decreased the FBF only at large doses. The results suggested that Sco may cause a selective dilatation of cerebral blood vessels.

Scoparone (6,7-dimethoxycoumarin 1.25, 2.5, 5 mg.kg-1) influenced the cardiohemodynamic functions in anesthetized cats. After i.v. injection the LVP-dP/dt loops and blood pressure were decreased. Both the contractile and relaxant functions of the left ventricle were inhibited. These were demonstrated by the reduction of dP/dtmax, Vmax, Vce-dp40, LVSP, prolongation of LVET, diminution of -dP/dtmax, and extension of the constant time of isometric diastolic pressure decay (T value). The preload of the left ventricle, LVEDF, was raised and the afterload (MAP, TPB) was decreased: The systolic volume, systolic index, cardiac output, and cardiac index were decreased slightly. The parameters TTI and TTI x HR, which reflect the myocardial oxygen consumption, were reduced. Furthermore, the heart rate was decreased at 5 mg.kg-1. The results indicate that scoparone could suppress the myocardial activity.